KCNQ1 Variant F351C Detail

We estimate the penetrance of LQTS for KCNQ1 F351C is 75%. We are unaware of any observations of this variant in individuals. F351C is not present in gnomAD. F351C has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F351C around 75% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.37 1.0 -3 0.954 83
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT1 Other Disease
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

F351C has 34 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: some residues appear multiple times at different distances. This results from the fact that the functional KV7.1 channel is a homotetramer and occasionally the same residue from multiple subunits is present within the 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
346 10
349 11 S349W,
345 11 G345R, G345R, G345A,
261 11 E261K, E261D, E261D, E261G, E261Q,
342 11 L342F, L342P,
247 12 T247I,
260 12
348 12
350 13 G350V, G350R, G350R, G350W,
262 13 L262P, L262R, L262V,
264 13
249 13 R249S, R249S,
344 13 A344V, A344E,
347 13 L347P, L347R,
258 13 H258P, H258N, H258R, H258Y,
343 13 P343S, P343L, P343R,
265 13 T265I,
259 13 R259C, R259H, R259L, R259G,
246 14
253 14 S253A, S253P,
263 14
353 14 L353P,
256 14
252 14 G252R,
352 14
254 14 V254M, V254L, V254L,
341 14 A341V, A341E,
266 14 L266P,
359 15 Q359del,
339 15 F339del, F339S,
338 15 S338F,
248 15 W248C, W248C, W248R, W248R,
351 15 F351L, F351L, F351L, F351S,
257 15 I257V,